ArticlePLoS biology2020
Blood-brain barrier genetic disruption leads to protective barrier formation at the Glia Limitans.
Article in PLoS biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 46 citations in OpenAlex.
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- The 129S1/SvlmJ mouse strain recapitulates severe hypertensive target organ damage under moderate angiotensin II-induced hypertension.Scientific reports · 2026Article
- Diverse roles of connexins in the neuro-vasculature in homeostasis and disease.Translational neuroscience · 2026Review
- 3DFrontiers in pharmacology · 2025Review
- Astrocytic DLL4-NOTCH1 signaling pathway promotes neuroinflammation via the IL-6-STAT3 axis.Journal of neuroinflammation · 2024Article
- Endothelial EGLN3-PKM2 signaling induces the formation of acute astrocytic barrier to alleviate immune cell infiltration after subarachnoid hemorrhage.Fluids and barriers of the CNS · 2024Article
- A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer's disease, and their co-morbidities.Frontiers in pharmacology · 2024Review
- A novel histone deacetylase inhibitor W2A-16 improves the barrier integrity in brain vascular endothelial cells.Frontiers in cellular neuroscience · 2024Article
- Astrocyte Involvement in Blood-Brain Barrier Function: A Critical Update Highlighting Novel, Complex, Neurovascular Interactions.International journal of molecular sciences · 2023Review
- Blood-Brain Barrier Breakdown in Alzheimer's Disease: Mechanisms and Targeted Strategies.International journal of molecular sciences · 2023Review
- Do astrocytes act as immune cells after pediatric TBI?Neurobiology of disease · 2023Review
- Psychosocial Basis of Human Sufferings and Poverty in Patients with Neurological and Psychiatric Disorders.Medical research archives · 2023Article
- EphA4/EphrinB2 signaling mediates pericyte-induced transient glia limitans formation as a secondary protective barrier after subarachnoid hemorrhage in mice.Experimental neurology · 2023Article
- Reconsidering the role of blood-brain barrier in Alzheimer's disease: From delivery to target.Frontiers in aging neuroscience · 2023Review
- Astrogliosis in multiple sclerosis and neuro-inflammation: what role for the notch pathway?Frontiers in immunology · 2023Review
- TargetingJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2022Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Inflammation of the central nervous system (CNS) induces endothelial blood-brain barrier (BBB) opening as well as the formation of a tight junction barrier between reactive astrocytes at the Glia Limitans. We hypothesized that the CNS parenchyma may acquire protection from the reactive astrocytic Glia Limitans not only during neuroinflammation but also when BBB integrity is compromised in the resting state. Previous studies found that astrocyte-derived Sonic hedgehog (SHH) stabilizes the BBB during CNS inflammatory disease, while endothelial-derived desert hedgehog (DHH) is expressed at the BBB under resting conditions. Here, we investigated the effects of endothelial Dhh on the integrity of the BBB and Glia Limitans. We first characterized DHH expression within endothelial cells at the BBB, then demonstrated that DHH is down-regulated during experimental autoimmune encephalomyelitis (EAE). Using a mouse model in which endothelial Dhh is inducibly deleted, we found that endothelial Dhh both opens the BBB via the modulation of forkhead box O1 (FoxO1) transcriptional activity and induces a tight junctional barrier at the Glia Limitans. We confirmed the relevance of this glial barrier system in human multiple sclerosis active lesions. These results provide evidence for the novel concept of "chronic neuroinflammatory tolerance" in which BBB opening in the resting state is sufficient to stimulate a protective barrier at the Glia Limitans that limits the severity of subsequent neuroinflammatory disease. In summary, genetic disruption of the BBB generates endothelial signals that drive the formation under resting conditions of a secondary barrier at the Glia Limitans with protective effects against subsequent CNS inflammation. The concept of a reciprocally regulated CNS double barrier system has implications for treatment strategies in both the acute and chronic phases of multiple sclerosis pathophysiology.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.